Schizophrenia is a devastating neurodevelopmental disorder affecting approximately 1% of the population. While the emergence of antipsychotics such as haloperidol, clozapine, and olanzapine has improved the lives of people suffering from this disease, these drugs are not effective on all symptom domains, and they have a range of serious side effects, including cardiovascular, metabolic, immunological, and neurologic effects. Therefore, new treatment options, particularly therapeutics targeting the negative and cognitive symptom domains, are desperately needed. Recent genetic and pharmacological studies have demonstrated that catechol-O-methyl transferase (COMT) plays a significant role in regulating prefrontal cortical dopamine levels, which are important for several aspects of cognition that are impaired in schizophrenia. COMT inhibition has been shown to improve working memory in preclinical and clinical studies; however, the current clinically available COMT inhibitors suffer from poor pharmacokinetics, inadequate brain penetration, and liver toxicity. Based on preliminary studies that have identified new COMT inhibitor leads, we propose to design novel COMT inhibitors that are optimized in terms of potency, selectivity, brain penetration, and pharmacokinetics. We propose a comprehensive research program that will design, synthesize and test new COMT inhibitors for potency, selectivity, brain penetration, and pharmacokinetics based on our new leads (Specific Aims 1 and 3). Structural biology and modeling studies will better define differences between the membrane-bound and soluble forms of COMT (Specific Aim 2) and contribute to design of new inhibitors. Leading compounds will be evaluated in rodent models of behavior to assess improvements in cognition as well as to evaluate confounding side effects (Specific Aim 4). The iterative cycle of drug discovery will lead to identification of a compound that can not only explore the role of COMT inhibition in the context of in vivo cognition models, but also be a candidate for clinical development. This project is ultimately directed toward the discovery of a novel treatment for the debilitating cognitive impairment seen in many patients with schizophrenia, for which there are currently no effective options. The compounds identified here will not only allow us to explore the role of COMT inhibition in the context of in vivo cognition models but also serve as drug candidates for preclinical evaluation as novel treatments for cognitive impairment in schizophrenia.